Uematsu Satoshi, Sato Shintaro, Yamamoto Masahiro, Hirotani Tomonori, Kato Hiroki, Takeshita Fumihiko, Matsuda Michiyuki, Coban Cevayir, Ishii Ken J, Kawai Taro, Takeuchi Osamu, Akira Shizuo
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita Osaka 565-0871, Japan.
J Exp Med. 2005 Mar 21;201(6):915-23. doi: 10.1084/jem.20042372. Epub 2005 Mar 14.
Toll-like receptors (TLRs) recognize microbial pathogens and trigger innate immune responses. Among TLR family members, TLR7, TLR8, and TLR9 induce interferon (IFN)-alpha in plasmacytoid dendritic cells (pDCs). This induction requires the formation of a complex consisting of the adaptor MyD88, tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and IFN regulatory factor (IRF) 7. Here we show an essential role of IL-1 receptor-associated kinase (IRAK)-1 in TLR7- and TLR9-mediated IRF7 signaling pathway. IRAK-1 directly bound and phosphorylated IRF7 in vitro. The kinase activity of IRAK-1 was necessary for transcriptional activation of IRF7. TLR7- and TLR9-mediated IFN-alpha production was abolished in Irak-1-deficient mice, whereas inflammatory cytokine production was not impaired. Despite normal activation of NF-kappaB and mitogen-activated protein kinases, IRF7 was not activated by a TLR9 ligand in Irak-1-deficient pDCs. These results indicated that IRAK-1 is a specific regulator for TLR7- and TLR9-mediated IFN-alpha induction in pDCs.
Toll样受体（TLRs）识别微生物病原体并触发先天免疫反应。在TLR家族成员中，TLR7、TLR8和TLR9在浆细胞样树突状细胞（pDCs）中诱导干扰素（IFN）-α。这种诱导需要形成一个由衔接蛋白髓样分化因子88（MyD88）、肿瘤坏死因子（TNF）受体相关因子6（TRAF6）和干扰素调节因子（IRF）7组成的复合物。在此我们展示了白细胞介素-1受体相关激酶（IRAK）-1在TLR7和TLR9介导的IRF7信号通路中的关键作用。IRAK-1在体外直接结合并磷酸化IRF7。IRAK-1的激酶活性对于IRF7的转录激活是必需的。在Irak-1缺陷小鼠中，TLR7和TLR9介导的IFN-α产生被消除，而炎性细胞因子的产生未受损害。尽管核因子κB（NF-κB）和丝裂原活化蛋白激酶正常激活，但在Irak-1缺陷的pDCs中，IRF7未被TLR9配体激活。这些结果表明，IRAK-1是pDCs中TLR7和TLR9介导的IFN-α诱导的特异性调节因子。
